Dirk Dittmer, PhD

Professor12-038LCCCCB#7295919-966-7960

Research

Approximately 1/3 of all human cancers is of viral origin or requires viral infection as an essential cofactor. The goal of our research is to understand viral cancers; specifically, cancers that are caused by Kaposi sarcoma-associated herpesvirus (KSHV).

KSHV is a double-stranded DNA virus with over 100 open reading frames, which belongs to human herpesviruses. It was discovered in 1994 by Patrick Moore and Yuan Chang, and is associated with Kaposi sarcoma (KS) as well as a B-cell lymphoma and multicentric Castleman’s disease (MCD). These diseases are rapidly fatal as they affect internal organs. In the U.S., KS is seen in the context of immune suppression such as in HIV-positive individuals or transplant patients. In parts of Sub-Saharan Africa KS is the most common cancer in males and also seen in children.

Our lab is focused on four areas:

1 Viral Genomics – To determine the genetics of AIDS-associated cancers we have developed real-time quantitative PCR-based arrays and NextGen Sequencing approaches. These allow us to analyze patterns of gene expression and mutation. We established the UNC Vironomics core (http://www.med.unc.edu/vironomics). We also use this technology in conjunction with NextGen sequencing to study microRNAs in Kaposi sarcoma and AIDS lymphoma.

2 Hunt for new viruses – We are trying to identify novel viruses in the human population though a combination of bioinformatics and robot-assisted screening. To date, have identified a novel primate KSHV homolog in primates as well as a novel SV40 homolog.

3 Regulation of viral latency – We initially demonstrated that the KSHV latency associated nuclear antigen (LANA) is transcribed in every single KS tumor cell. LANA is required for latent viral replication and proper episome segregation. Since the LANA promoter is the major latency promoter of KSHV, we are engaged in a detailed investigation of its architecture and regulation by cellular factors, such as p53, Sp1 as well as LANA itself.

4 Mouse models of KSHV oncogenesis and pre-clinical drug development – We have developed transgenic mice, which express the LANA protein under the control of its own promoter and had previously shown that the LANA promoter exhibits B-lineage specificity in transgenic mice. We use this model in conjunction with specific ko-mice to study the immune regulation by KSHV. Building upon or initial studies of SCID-human mouse models for primary KSHV infection, we established a xenograft model for KSHV-associated lymphomas and KS. Using this model we are investigating the anti-lymphoma properties of established and novel anti-viral drugs.